Proton therapy (PT) is a latest state-of-art radiation therapy that can focus high level radiations to a small target. In principle, this unique physical property will allow PT to become a targeted therapy for significantly improved therapy efficacy while simultaneously reduced dose to normal tissues and thus reduced treatment complications. However, there are inherent physical uncertainties with PT which could make PT be harmful to a patient if the high dose were not delivered accurately. Clinicians have been forced to take overly conservative treatment approaches in restricting doses to the tumor in order to ensure sparing of normal tissues. It is critically important to overcome this impediment in order to dramatically enhance PT therapeutic outcomes and achieve the full clinical benefits. This research project aims to study the feasibility of an innovative PET image-based on-line verification of PT treatment plan instead of current off-line method. Conceptually, on-line approach will directly measure the potential deviation of actual setup and beam range (where beam will stop) from the treatment plan before the start of treatment, which will most effectively improve the targeting accuracy of PT and significantly enhance the PT therapy efficacy. Nevertheless, technically, it is challenging to achieve on-line measurement with two major technical questions have not been seriously investigated: Can a PET perform well in such proton radiation environment? Can on-line measurement with substantially lower count statistics provide the same level of measurement accuracy and precision as off-line measurement provides? This project attempts to answer these critical questions by pursuing three specific aims: scaling up an existing prototype PET to enable on-line imaging feasibility study; conducting phantom experimental studies under different proton radiation and PET imaging conditions to assess the feasibility of on-line measurement and PET performance; investigating the technical requirement to achieve on-line measurement under clinically relevant radiation and imaging conditions. The outcome of this research is expected to provide vital information on the feasibility of on-line measurement, gain the perspective of its potential for a high impact clinica application, and assist future technology development.